title: Progressive changes in chromatin structure and DNA damage response signals in bone marrow and peripheral blood during myelomagenesis.
abstract: The molecular pathways implicated in multiple myeloma (MM) development are rather unknown. We studied epigenetic and DNA damage response (DDR) signals at selected model loci (N-ras, p53, d-globin) in bone marrow plasma cells and peripheral blood mononuclear cells (PBMCs) from patients with monoclonal gammopathy of undetermined significance (MGUS; n=20), smoldering/asymptomatic MM (SMM; n=29) and MM (n=18), as well as in healthy control-derived PBMCs (n=20). In both tissues analyzed, a progressive, significant increase in the looseness of local chromatin structure, gene expression levels and DNA repair efficiency from MGUS to SMM and finally to MM was observed (all P<0.002). Following ex vivo treatment with melphalan, a gradual suppression of the apoptotic pathway occurred in samples collected at different stages of myelomagenesis, with the severity and duration of the inhibition of RNA synthesis, p53 phosphorylation at serine15 and induction of apoptosis being higher in MGUS than SMM and lowest in MM patients (all P<0.0103). Interestingly, for all endpoints analyzed, a strong correlation between plasma cells and corresponding PBMCs was observed (all P<0.0003). We conclude that progressive changes in chromatin structure, transcriptional activity and DDR pathways during myelomagenesis occur in malignant plasma cells and that these changes are also reflected in PBMCs.
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA [2] Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece.
authors.forename: M
authors.initials: M
authors.lastname: Gkotzamanidou
authors.affiliation: Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece.
authors.forename: E
authors.initials: E
authors.lastname: Terpos
authors.affiliation: Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, University of Athens, Athens, Greece.
authors.forename: C
authors.initials: C
authors.lastname: Bamia
authors.affiliation: Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
authors.forename: S A
authors.initials: SA
authors.lastname: Kyrtopoulos
authors.affiliation: First Department of Propedeutic Medicine, School of Medicine, Athens, Greece.
authors.forename: P P
authors.initials: PP
authors.lastname: Sfikakis
authors.affiliation: Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece.
authors.forename: M A
authors.initials: MA
authors.lastname: Dimopoulos
authors.affiliation: Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
authors.forename: V L
authors.initials: VL
authors.lastname: Souliotis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D001853:Bone Marrow / Q000473:pathology*; D002843:Chromatin / Q000737:chemistry*; D004249:DNA Damage; D017931:DNA Primers; D004260:DNA Repair; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics / Q000473:pathology*; D010766:Phosphorylation
chemical_list: D002843:Chromatin; D017931:DNA Primers